Animal models in the investigation of anorexia

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Abstract

Anorexia nervosa (AN) is an eating disorder of unknown origin that most commonly occurs in women and usually has its onset in adolescence. Patients with AN invariably have a disturbed body image and an intense fear of weight gain. There is currently no definitive treatment for this disease, which carries a 20% mortality over 20 years. Development of an appropriate animal model of AN has been difficult, as the etiology of this eating disorder likely involves a complex interaction between genetic, environmental, social, and cultural factors. In this review, we focus on several possible rodent models of AN. In our laboratory, we have developed and studied three different mouse models of AN based on clinical profiles of the disease; separation stress, activity, and diet restriction (DR). In addition, we discuss the spontaneous mouse mutation anx/anx and several mouse gene knockout models, which have resulted in an anorexic phenotype. We highlight what has been learned from each of these models and possibilities for future models. It is hoped that a combination of the study of such models, together with genetic and clinical studies in patients, will lead to more rational and successful prevention/treatment of this tragic, and often fatal, disease.

Introduction

Anorexia nervosa (AN) is a tragic and debilitating disease that affects mainly teenage girls and begins around the age of puberty. The disease usually begins with “harmless” efforts at dieting which then gets out of control. This excessive dieting is associated with a distorted image of their bodies, believing themselves to be too fat even when severely underweight, which creates a vicious cycle. The major clinical symptoms of AN are a lowered body weight, obsessional preoccupation with food, an unreasonable fear of fatness, amenorrhea, bradycardia, abnormal blood pressure and temperature, and often significant depression [1]. There are two principal clinical types—restrictive and binge/purging—and patients often also use excessive physical activity to promote a further negative energy balance. AN is a disorder of unknown etiology, but evidence suggests multifactorial causes based on culture, environment, biology, and genetic predisposition in its development [2]. Thus, anorexia involves psychological, physiological, and sociocultural antecedents, which makes it a mirror of the prevailing society values [3]. AN is a disease affecting adolescent development and social function; it has a significant mortality and is very difficult to treat [4].

Development of an appropriate animal model of AN has been difficult, as the etiology of this eating disorder likely involves a complex interaction between genetic, environmental, social, and cultural factors. While no animal will in fact starve to death voluntarily, there are examples of prolonged self-starvation over periods of months which are related to reproductive behavior (seals, penguins, whales, octopus), seasonal migration (birds), or hibernation [5]. Instead of a model based on cause, researchers have turned to animal models which mimic some of the important aspects of the human syndrome. For the case of AN, that would include adolescent onset of the disease, predominance in females, decreased food intake, decreased body weight, increased activity, and abnormal neuroendocrine function to name just the major attributes. As is seen in many human disease models, very few animal models have succeeded in encompassing all the aspects of the disease, although they still have been considered useful in studying diseased states. This is clearly seen in animal models of obesity, which include obesity due to neurological damage, genetic mutation, dietary manipulations, and drug treatment. None of the present animal models of obesity are ideal models of the human condition (there can never be of course a psychological dimension), but each model contributes another aspect to our understanding of the disease. The fact that there are similarities between obesity and AN, such as problems in eating and body weight, lends encouragement to the development and use of such animal models also for the study of AN.

In this review, we will only focus on rodent models of AN, which are the most common species used in research on eating behavior and body weight. In our laboratory, we have developed and studied three different mouse models of AN, which involve environmental manipulations. For the genetic models, mouse models have dominated the field, due to the advances in technology and knowledge in mouse genetics.

The work in our laboratory during the past 9 years uses a biophysiological approach to AN that is based on the hypothesis that some of the symptoms are caused by malnutrition and a lack of essential dietary precursors of neurotransmitters. These, in turn, affect both cognitive function and energy regulation. We have studied the effects of tyrosine supplementation on these functions through influence on the major neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT) and their intermediates. Lately, we have also studied effects on the endocannabinoid system, which is based mainly on derivatives of the essential n−6 fatty acid arachidonate using its amide, ester and ether.

Section snippets

Stress models

Models of anorexia based on stress include stresses such as tail pinching, cold swimming with or without food deprivation [6], and direct brain stimulation, either through injection or electrical stimulation [7], [8]. Certain disadvantages may be seen in these animal models of weight loss. Those using aversive stimuli may physically harm the animals. Temporary stress might affect mechanisms in the body that regulate energy expenditure and food intake. Injection of morphine or electrical

Genetic mouse models

In recent years, there has been a burst of information regarding the genetics of regulation of food intake and energy balance. Many genes have been identified and cloned and their gene products characterized. In the mouse, mutations in many of these genes have resulted in an obesity phenotype. In contrast, there has been less of a focus on genetic models of anorexia. There are far fewer genetic rodent models that succeed in shifting the regulation of food intake, satiety, or metabolic turnover

Gene knockout models

Some gene disruption experiments have been performed with the goal of perturbing the food consumption and energy pathway, while others have unexpectedly resulted in an anorexic phenotype. Regardless of whether the phenotype was expected or not, these gene knockout models have clear advantages and disadvantages. An advantage of a genetic model is that a single gene is perturbed, and sometimes with tissue or cell type specificity. Therefore, there is a direct connection between the gene and the

Combination genetic/environmental models

The two genetic models, Crhr2 deficient [50] and CB1 deficient mice [52], did not initially show an atypical feeding phenotype. The eating phenotype in these genetic models was only uncovered after temporary food restriction. Normal mice after a period of fasting respond by compensatory hyperphagia during the first few hours of refeeding. These mutant mice showed less of the hyperphagic behavior. This may represent an interaction of genetics (the genetic lesion) and environment (food

Conclusion

This account of animal models of anorexia is by no means exhaustive but rather the examples have been chosen to highlight possible models and possible combination of models that will aid in the further study of anorexia. Although no single model has proven to be the ideal model for the study of anorexia, these models confirm that both genetic and environmental factors can contribute to an anorexia phenotype. There is no simple cause of AN, and most likely, genetic, environmental, and social

Acknowledgements

The research in our laboratory was supported by the United States–Israel Binational Science Foundation (9400140) and the Israeli Ministry of Health.

References (53)

  • U. Schweiger et al.

    Brain tyrosine availability and the depression of central nervous norepinephrine turnover in acute and chronic starvation in adult male rats

    Brain Res.

    (1985)
  • C.L.C. Nascimento et al.

    Acetylcholine and related enzymes from neonatal malnourished rat cerebral-cortex

    Nutr. Res.

    (1991)
  • S.Z. Hao et al.

    Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice

    Eur. J. Pharmacol.

    (2000)
  • Y. Avraham et al.

    Behavioral and neurochemical alterations caused by diet restriction—the effect of tyrosine administration in mice

    Brain Res.

    (1996)
  • J.E. Johansen et al.

    Hypothalamic CART and serum leptin levels are reduced in the anorectic (anx/anx) mouse

    Mol. Brain Res.

    (2000)
  • J.W. Jahng et al.

    Neuropeptide Y mRNA and serotonin innervation in the arcuate nucleus of anorexia mutant mice

    Brain Res.

    (1998)
  • J.H. Son et al.

    Drastic and selective hyperinnervation of central serotonergic neurons in a lethal neurodevelopmental mouse mutant, anorexia (anx)

    Mol. Brain Res.

    (1994)
  • M.S. Szczypka et al.

    Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice

    Neuron

    (2001)
  • E.M. Berry et al.

    Tetrahydrocannabinol and endocannabinoids in feeding and appetite

    Pharmacol. Ther.

    (2002)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders: DSM-IV

    (1994)
  • D.M. Garner et al.

    Cognitive–behavioral therapy for anorexia nervosa

  • J. Griffin et al.

    A modern day holy anorexia? Religious language in advertising and anorexia nervosa in the West

    Eur. J. Clin. Nutr.

    (2003)
  • N. Mrosovsky et al.

    Animal anorexias

    Science

    (1980)
  • G.P. Smith

    Animal-models of human eating disorders

    Ann. N.Y. Acad. Sci.

    (1989)
  • D. Pierce et al.

    Activity anorexia—an animal model and theory of human self starvation

  • A. Routtenberg et al.

    Self-starvation of rats living in activity wheels on a restricted feeding schedule

    J. Comp. Physiol. Psychol.

    (1967)
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